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Molecular Pharmacology

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Research ArticleArticle

Cisplatin-Induced DNA Damage Activates Replication Checkpoint Signaling Components that Differentially Affect Tumor Cell Survival

Jill M. Wagner and Larry M. Karnitz
Molecular Pharmacology July 2009, 76 (1) 208-214; DOI: https://doi.org/10.1124/mol.109.055178
Jill M. Wagner
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Larry M. Karnitz
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Abstract

Cisplatin and other platinating agents are some of the most widely used chemotherapy agents. These drugs exert their antiproliferative effects by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The cross-links mobilize signaling and repair pathways, including the Rad9-Hus1-Rad1-ATR-Chk1 pathway, a pathway that helps tumor cells survive the DNA damage inflicted by many chemotherapy agents. Here we show that Rad9 and ATR play critical roles in helping tumor cells survive cisplatin treatment. However, depleting Chk1 with small interfering RNA or inhibiting Chk1 with 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide (AZD7762) did not sensitize these cells to cisplatin, oxaliplatin, or carboplatin. Moreover, when Rad18, Rad51, BRCA1, BRCA2, or FancD2 was disabled, Chk1 depletion did not further sensitize the cells to cisplatin. In fact, Chk1 depletion reversed the sensitivity seen when Rad18 was disabled. Collectively, these studies suggest that the pharmacological manipulation of Chk1 may not be an effective strategy to sensitize tumors to platinating agents.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA084321] and the Mayo Foundation.

  • ABBREVIATIONS: TLS, translesion synthesis; 9-1-1, Rad9-Hus1-Rad1; FA, Fanconi's anemia; HR, homologous recombination; siRNA, small interfering RNA; AZD7762, 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; ES, embryonic stem.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Accepted April 28, 2009.
    • Received January 29, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (1)
Molecular Pharmacology
Vol. 76, Issue 1
1 Jul 2009
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Research ArticleArticle

Cisplatin-Induced DNA Damage Activates Replication Checkpoint Signaling Components that Differentially Affect Tumor Cell Survival

Jill M. Wagner and Larry M. Karnitz
Molecular Pharmacology July 1, 2009, 76 (1) 208-214; DOI: https://doi.org/10.1124/mol.109.055178

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Research ArticleArticle

Cisplatin-Induced DNA Damage Activates Replication Checkpoint Signaling Components that Differentially Affect Tumor Cell Survival

Jill M. Wagner and Larry M. Karnitz
Molecular Pharmacology July 1, 2009, 76 (1) 208-214; DOI: https://doi.org/10.1124/mol.109.055178
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